Genetic Associations and Mechanisms in Oncology (GAME-ON): A Network of Consortia for Post-Genome Wide Association (Post-GWA) Research

Background and Overall Goals

Genome-wide association studies (GWAS) involve rapidly scanning markers across the complete genomes of a large number of cases and controls to find common genetic variations associated with a particular disease. Since 2005, such studies have identified a large number of loci with common genetic variants associated with cancer risk. However, the variants identified by these studies are usually markers and not the causal variants themselves. In addition, the biological mechanisms through which the associated loci confer cancer risk are often unknown. Lastly, the modulating effect of environmental and lifestyle factors need to be taken into account when estimating the risk conferred by the causal variants.

The Genetic Associations and Mechanisms in Oncology (GAME-ON) initiative was launched by NCI in 2010 in response to RFA-CA-09-002, and it is jointly supported by the Epidemiology and Genomics Research Program and the Division of Cancer Biology. GAME-ON's overall goal is to foster an intra-disciplinary and collaborative approach to the translation of promising research leads deriving from the initial wave of cancer GWAS.

Phases of the Post-GWASResearch ContinuumClick to enlarge.

The long-term goal of the GAME-ON initiative is to provide a rigorous knowledge base that will enable clinical translation and public health dissemination of the GWAS findings. This goal is being achieved by teams of epidemiologists, basic scientists, and clinicians, collaborating on follow-up investigations of genomic regions that have been implicated in susceptibility to certain cancer types. The post-GWAS continuum of research addressed by this network of consortia includes:

Replication of previous findings and identification of new susceptibility loci through pooled or meta analyses and extension of GWAS to diverse populations

Fine mapping of identified loci to better pinpoint causal variants

Unraveling the function of identified genetic variants through functional and animal models studies

Examining the effect of gene-gene and gene-environment interplay in modulating the risk of disease, and

Using the knowledge acquired from these studies to develop risk prediction mechanisms that can be used by the general population and in clinics.

Funded Projects, Working Groups, and Organizational Structure

Three Areas of thePost-GWAS ContinuumClick to enlarge.

There are currently five cooperative agreements (U19) funded through the GAME-ON initiative. Each U19 includes three projects focusing on the genomic, functional, and epidemiologic follow-up of GWAS of breast, prostate, colon, lung and ovarian cancers.

Funded Projects

Click the links below each of the following project names to view brief descriptions of each project, links to more detailed abstracts, and key personnel lists.

The CORECT project is investigating and identifying susceptibility loci for colorectal cancer in order to characterize the biologic basis of inherited susceptibility and recognize how genetic variation may be quantified and modified by genetic and environmental risk factors. Complex models that take advantage of this new genetic information, together with known environmental factors for colorectal cancer, will expedite the translation of these findings into clinical practice.

The DRIVE project is systematically discovering and replicating additional common genetic variants associated with breast cancer, assessing their biological significance, and developing evidence-based assessments of the clinical validity of prediction algorithms using these variants, as well as investigating their suitability for translation into clinical practice.

The ELLIPSE project is pursuing thorough identification and characterization of genomic loci associated with prostate cancer. The overarching goal is to discover the pathways that drive prostate cancer pathogenesis and to assess their role in clinical decision making.

GWAS have successfully identified many common susceptibility alleles for multiple disease phenotypes, including the identification of genes involved in pathways not previously implicated in cancer. This has not been possible for ovarian cancer, but the recent completion of several independent GWAS, with the potential for replication in participating Ovarian Cancer Association Consortium (OCAC) sites, provides the opportunity to identify such alleles and match the success for other cancers.

The TRICL project is integrating data from eight GWAS studies on lung cancer to increase power to detect genetic factors influencing all types of lung cancer and to be able to analyze specific subsets, such as cases with early onset, specific histological sets, gender-defined groups, and never smokers. The extended sample size will allow study of gene-environment interactions. The goal is to identify individuals at high risk for lung cancer for whom screening and early detection would be most beneficial.

Working Groups and Organizational Structure

GAME-ONOrganizational StructureClick to enlarge.

There are six GAME-ON Working Groups that cut across all five projects that promote scientific collaborations in specific areas across cancer types:

An Executive Committee composed by the Lead Investigators of the five U19s establishes the policies and processes across the initiative. NCI has appointed an External Advisory Committee to provide advice on the overall initiative progress.

The GAME-ON organizational structure allows for vertical and horizontal dissemination of knowledge and expertise.

Participating Consortia

The GAME-ON initiative is one of the many ways in which EGRP works to facilitate collaborative research through a network of cancer epidemiology consortia. To maximize the scientific benefit and impact of the GAME-ON program, funded investigators must agree to data sharing requirements as outlined in the general NIH and NCI policies for sharing large data sets. For questions related to GAME-ON data sharing, contact Stefanie Nelson, Ph.D..

Research Tools and Other Research Resources

Investigators are also developing analytic software and tools that can be used by the scientific community at large. The GAME-ON Initiative maintains a list of related research resources that may be valuable to investigators interested in post-GWAS research.